Evidence map›Paper›PMID 41015034›Full record

ArticleCell reports. Medicine2025

Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease.

Letizia Fontana, Pierre Martinucci, Simone Amistadi, Tristan Felix, Margaux Mombled, Alexandra Tachtsidi, Guillaume Corre, Anne Chalumeau, Giulia Hardouin, Jeanne Martin and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports. Medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. bioRxiv : the preprint server for biology · 2026
    Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Letizia FontanaUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France.
Pierre MartinucciUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France.
Simone AmistadiUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France.
Tristan FelixUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France.
Margaux MombledGenethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France.
Alexandra TachtsidiGenethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France.
Guillaume CorreGenethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France.
Anne ChalumeauUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France.
Giulia HardouinUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France.
Jeanne MartinUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France.
Oriana RomanoDepartment of Molecular Medicine, University of Padova, 35122 Padova, Italy.
Mario AmendolaGenethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France; Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy.
Panagiotis AntoniouUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France. Electronic address: pantonioy91@gmail.com.
Annarita MiccioUniversité Paris Cité, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR 1163, 75015 Paris, France. Electronic address: annarita.miccio@institutimagine.org.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Sickle cell disease (SCD) is a genetic anemia caused by the production of an abnormal adult hemoglobin. Elevated levels of fetal hemoglobin (HbF) in adulthood reduce disease severity. A promising therapy involves the treatment of hematopoietic stem/progenitor cells (HSPCs) with CRISPR-Cas9 to downregulate the HbF repressor BCL11A via generation of double-strand breaks (DSBs) in the +58-kb enhancer. To improve safety and HbF induction, we use base editors to target both the +58-kb and +55-kb enhancers without generating DSBs. We dissect key DNA motifs recognized by transcriptional activators and identify critical nucleotides. Multiplex base editing efficiently disrupts these sites, reactivating HbF to levels exceeding those achieved with CRISPR-Cas9-induced editing, while minimizing DSBs and genomic rearrangements. Base editing is effective in long-term repopulating HSPCs and results in robust HbF reactivation in vivo. These findings demonstrate that multiplex base editing of BCL11A enhancers is a safe, efficient, and durable strategy to treat SCD.

Indexed as

Anemia, Sickle CellCarrier ProteinsGene EditingRegulatory Sequences, Nucleic AcidRepressor ProteinsAnimalsCRISPR-Cas SystemsDNA Breaks, Double-StrandedFetal HemoglobinHematopoietic Stem CellsHumansMiceBCL11A protein, humanCarrier ProteinsFetal HemoglobinRepressor Proteinsbase editingBCL11Afetal hemoglobingene editinghematopoietic stem cellssickle cell disease

Identifiers

PMID41015034
PMCPMC12629801

What OpenQuestion holds

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LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.